Search Results (38,700)

Coronary artery disease is a leading cause of morbidity and mortality in modern medicine. In contrast, surgical myocardial revascularization via coronary artery bypass grafting (CABG) remains the gold standard of treatment for complex multivessel disease. The great saphenous vein remains the most frequently used conduit due to its availability and technical simplicity, but its long-term patency is significantly inferior to that of arterial grafts. The primary pathological process responsible for vein graft failure is intimal hyperplasia, which represents a complex response of the vascular wall to surgical trauma, vein arterialization, inflammation, and hemodynamic stress. This process is characterized by endothelial dysfunction, inflammatory cell activation, proliferation and migration of vascular smooth muscle cells, and extracellular matrix remodeling. Underpinning these alterations are numerous molecular pathways, including NF-κB, MAPK, PI3K/Akt, TGF-β, and mTOR signaling, as well as substantial contributions from oxidative stress, cytokines, growth factors, and microRNAs. Contemporary research indicates that the phenotypic transformation of vascular smooth muscle cells constitutes the central event in the development of intimal hyperplasia. Understanding the cellular and molecular mechanisms underlying this disease’s onset enables the development of novel therapeutic strategies to preserve long-term graft patency. This review paper aims to provide a systematic overview of current knowledge regarding the molecular and cellular mechanisms of intimal hyperplasia development in vein grafts following CABG. Full article

Sertoli cells (SCs) are essential for spermatogenesis and provide structural and nutritional support to germ cells in the Chinese Holstein cattle testis. Although microRNAs (miRNAs) are known to regulate SC function, the specific role of Bta-miR-146a in bovine SCs is unclear. This study investigated the mechanisms by which Bta-miR-146a regulates bovine immature SCs. Using molecular cloning, we constructed Bta-miR-146a overexpression and interference vectors and transfected them into SCs via lipofection. Quantitative real-time PCR (RT-qPCR), 5-ethynyl-2′-deoxyuridine (EdU) proliferation assays, Cell Counting Kit-8 (CCK-8) viability assays, and flow cytometry revealed that Bta-miR-146a overexpression inhibited SC proliferation and promoted apoptosis, whereas Bta-miR-146a inhibition increased proliferation and suppressed apoptosis. Dual-luciferase reporter assays confirmed that SMAD4 is a direct target of Bta-miR-146a; SMAD4 interference reduced SC proliferation and increased apoptosis, whereas overexpression had the opposite effect. Furthermore, activity of this gene modulates the TGFβ/MAPK signaling pathway; SMAD4 interference reduces the expression of TGFβ, TGF-βRII, DAXX, MAP3K5, P38, and MAX. These findings indicate that the Bta-miR-146a/SMAD4/TGFβ/MAPK axis is a key regulator of SC proliferation and apoptosis, offering insights into the molecular mechanisms underlying bovine spermatogenesis and potential targets for improving reproductive performance. Full article

Spinal cord injury (SCI) research has long treated the glial scar as the central obstacle to regeneration. That view is useful, but it is now too narrow. The scar is not a passive wall. It is an evolving repair tissue that contains inflammation, stabilizes the lesion, remodels extracellular matrix, and, under many conditions, restricts axonal growth. The next phase of SCI therapy should therefore move from scar suppression to scar reprogramming. In this Opinion, I argue that the field should prioritize temporally precise, spatially targeted, and biomarker-guided interventions that preserve the protective functions of the scar while reducing its chronic inhibitory features. Cell transplantation, biomaterials, neurotrophic factors, gene therapy, immunomodulation, and neuromodulation each offer important strengths, but none is sufficient as a stand-alone regenerative therapy. The most credible path forward is a staged combinatorial strategy that converts the lesion microenvironment into a permissive, instructive, and trainable tissue bridge. Full article

Insufficient vascularization remains a major limitation in tissue engineering, restricting the survival and maturation of larger bioengineered constructs. While candidate hydrogels are commonly characterized with regard to physicochemical properties, gelation behavior, mechanical performance, and cytocompatibility, simple functional assays that assess their capacity to support vascular sprouting are less frequently integrated into early-stage biomaterial evaluation. Here, we investigated the established ex vivo aortic ring assay (ARA) as an exploratory functional approach for the initial comparison of selected hydrogel formulations. Murine aortic rings were embedded in collagen I (Col I), alginate (Alg), or gelatin methacryloyl (GelMA) and cultured under control conditions or with vascular endothelial growth factor A (VEGF-A) stimulation. These hydrogels were intentionally selected as a proof-of-concept panel of representative, non-equivalent material classes with distinct expected cell-interactive properties. After five days, Col I supported robust capillary-like outgrowth that was further enhanced by VEGF-A, whereas the tested GelMA formulation supported only limited cellular migration and the tested unmodified Alg formulation showed no detectable sprouting under the conditions examined. Cluster of differentiation 31 (CD31) immunostaining supported the presence of an endothelial component within the Col I-supported sprouting structures. These findings demonstrate that the ARA can detect pronounced formulation-dependent differences among the specific hydrogels tested using straightforward morphological and immunostaining readouts. Within the scope of the formulations tested, these findings support the ARA as a complementary functional readout alongside conventional biomaterial characterization before more complex tissue engineering or biofabrication studies are performed. Full article

New indazole and pyrazole nucleoside analogues were synthesized by enzymatic transglycosylation using E. coli purine nucleoside phosphorylase (PNP). Indazoles substituted at position 5 or 6 with bromine, pyrazole or pyrimidine fragments were used as heterocyclic bases. In the case of indazole-pyrazole hybrids, the selectivity of PNP in glycosylation of the pyrazole fragment, rather than the indazole one, was established. Molecular modeling methods allowed the identification of the preferred orientations of substrates in the active site of the enzyme, leading to the formation of N1- and N2-regioisomers of indazole. Unique substrate specificity ensured the possibility of glycosylation of the bases with conversion rates of 65–100% (according to HPLC analysis of the reaction mixtures) and isolated yields of 19–94%. It was shown that the synthesized nucleoside analogues are not inhibitors of E. coli adenosine deaminase (ADA). They do not exhibit cytotoxicity towards cancer cell lines (SH-SY5Y neuroblastoma cell lines, K-562 lymphoblastic cells, and HL-60 promyeloblastic cells). The activity of indazole derivatives against Mycobacterium tuberculosis (strain H37Rv) was determined by the microdilution method. 1-(β-D-2′deoxyribofuranosyl)-5-bromo-indazole and 5-(pyrimidin-5-yl)-1H-indazole at a concentration of 50 μg/mL were able to inhibit 50% and 90% of the culture growth, correspondingly. Full article

Panax ginseng, a high-value medicinal plant, faces substantial yield losses due to black spot disease, while conventional chemical controls cause pesticide residues and soil ecological damage, necessitating green biocontrol strategies. Here, two antagonistic strains, Bacillus sp. WY17 and WY26, were isolated from the surface-sterilized internal root tissues of 10-year-old ginseng. Through systematic optimization of carbon/nitrogen sources, inorganic salts, and fermentation parameters (temperature, pH, agitation, inoculum size, and duration), the optimal culture conditions were established. The optimal consortium consisted of WY17 and WY26 in a 2:1 ratio (WY17:WY26 = 2:1), which achieved an antifungal inhibition rate of 84.94% against the pathogen compared to the untreated control group (pathogen only). Mechanistic investigations revealed that the crude protein extract exerted its antifungal effect by compromising the integrity of the pathogen’s cell membrane, leading to increased permeability and leakage of intra-cellular contents, and produced cell wall-degrading enzymes (chitinase and β-1,3-glucanase), thereby inhibiting mycelial growth and spore germination. In vitro efficacy tests demonstrated that this crude protein extract performed comparably to the chemical fungicide 70% mancozeb, with no statistically significant difference observed between them (p > 0.05). These findings identify a promising compound biocontrol agent derived from indigenous Bacillus strains, offering an effective and environmentally friendly alternative for managing ginseng black spot disease. Full article

Widespread environmental contamination by per- and poly-fluoroalkyl substances (PFAS) has driven the phaseout of traditional long-chain compounds; however, the toxicity of their highly mobile, short-chain replacements to aquatic microorganisms remains less well characterized. This study compared the toxicity of perfluoroalkyl carboxylic acid (PFCA): long-chain perfluorooctanoic acid (PFOA, C8) and the short-chain perfluorobutanoic acid (PFBA, C4) in two structurally distinct microalgae, Prymnesium parvum and Chlorella sorokiniana. P. parvum was more sensitive to PFAS exposure than C. sorokiniana, with significant growth inhibition occurring at 25–50 mg/L and complete mortality at 100 mg/L, whereas C. sorokiniana exhibited significant effects at concentrations ≥200 mg/L. PFBA exhibited greater toxicity than PFOA in both species, with IC₅₀ values of 25.81 and 64.30 mg/L, respectively, in P. parvum and 101.4 and 277.1 mg/L, respectively, in C. sorokiniana. PFBA induced reactive oxygen species (ROS) generation, lipid peroxidation, and significantly increased in cell volume and chlorophyll content in P. parvum, whereas C. sorokiniana exhibited oxidative responses primarily at higher concentrations and no significant changes in cell dimensions or chlorophyll content. The responses indicate that oxidative stress is an important component of PFCA toxicity and sensitivity differs substantially between microalgal species. The contrasting responses may be associated with differences in cellular structure and physiology, although the underlying mechanisms require further investigation. Overall, PFCA toxicity was both compound- and species-dependent, and the greater toxicity of PFBA under the tested conditions demonstrates that short-chain replacement PFCAs should not be assumed to have lower biological toxicity than their long-chain counterparts. Full article

Background: Triple-negative breast cancer (TNBC) lacks effective targeted therapies, and its dependence on glycolysis represents a potential metabolic vulnerability. EIF3H, the largest subunit of the eukaryotic translation initiation factor 3 complex and a putative deubiquitinase, has been implicated in tumor progression, but its role in TNBC metabolism remains unclear. Methods: EIF3H expression and prognostic value were evaluated in public datasets, clinical TNBC specimens, and cell lines. Functional roles were examined using proliferation, colony formation, migration, and xenograft assays. Mechanisms were investigated by mass spectrometry, co-immunoprecipitation, ubiquitination and glycolytic rate assays, macrophage co-culture, and single-cell transcriptomic analysis. Results: EIF3H was significantly upregulated in TNBC and associated with poor survival. Transcriptionally activated by TRPS1, EIF3H bound to lactate dehydrogenase A (LDHA), reduced its ubiquitination, and prevented its proteasomal degradation. LDHA stabilization enhanced glycolysis and lactate production, thereby promoting TNBC cell proliferation and migration in vitro and tumor growth in vivo; these effects were abolished by LDHA knockdown and restored by LDHA re-expression. In addition, tumor-derived lactate induced M2 macrophage polarization via GPR65, which in turn reinforced malignant progression. Conclusions: Our findings define a TRPS1–EIF3H–LDHA axis that drives glycolysis-dependent TNBC progression and reveal lactate–GPR65 signaling as a mediator of tumor–macrophage crosstalk, supporting EIF3H as a potential prognostic biomarker and therapeutic target in TNBC. Full article

High-temperature stress impairs plant growth and alters secondary metabolism. Polymethoxyflavones (PMFs) are citrus-specific flavonoids with important nutritional benefits; however, their transcriptional responses to heat stress remain poorly understood. Here, five-month-old ‘Ponkan’ citrus seedlings were exposed to 40 °C for 6, 11, and 21 days. HPLC analysis showed that the accumulation of four major PMFs (sinensetin, nobiletin, tangeretin, and 5-demethylnobiletin) was significantly reduced in leaves under heat stress. RNA-seq identified 3424 differentially expressed genes shared across all three time points, which were enriched in pathways associated with microtubule cytoskeleton organization, cell cycle regulation, and glyoxylate and dicarboxylate metabolism. Further analysis of the PMF biosynthetic pathway revealed that 14 of 18 key structural genes, including CHS, CHI, FNSII, and OMT family members, were downregulated by heat treatment. In addition, several bHLH, AP2/EREBP, and MYB transcription factors, known regulators of flavonoid biosynthesis, exhibited expression patterns closely associated with PMF accumulation. RT-qPCR analysis validated the transcriptome results. Collectively, these findings suggest that heat stress suppresses PMF accumulation through coordinated repression of PMF biosynthetic genes and their potential regulators. This study provides new insights into the molecular basis of heat-responsive PMF metabolism and offers potential targets for maintaining citrus nutritional quality under elevated temperatures. Full article

Amniotic membranes are extensively used in feline corneal repair; however, challenges such as rapid degradation and difficulties with preservation across species limit their clinical use. The aim of this study was to develop a feline amniotic membrane-based graft with stem cell activity and provide experimental evidence for its potential use as a corneal epithelial transplant material in cats. FLSCs were first treated with different concentrations of epidermal growth factor (EGF), and 0.5 mg/L EGF was identified as the optimal concentration for promoting cellular activity. Under this condition, FLSCs exhibited enhanced proliferation and wound closure ability, with complete scratch closure observed approximately 24 h earlier than that in the control group. Growth curve analysis showed that FLSCs maintained stable proliferation characteristics, with a calculated population doubling time of approximately 25.2 h. Subsequently, FLSCs were seeded onto the lyophilized feline amniotic membrane scaffold. Light microscopy, scanning electron microscopy, and transmission electron microscopy demonstrated that FLSCs adhered to and proliferated on the scaffold, forming cell–matrix interaction structures, including hemidesmosome-like junctions. Immunofluorescence staining confirmed the expression of stem cell-associated markers ABCG2 and p63 after scaffold culture. These findings demonstrate the successful fabrication of a feline FLSC-loaded amniotic membrane construct in which FLSCs retained the expression of the examined limbal/stem cell-associated markers after scaffold culture. The successfully constructed FLSC-loaded feline amniotic membrane graft demonstrated considerable potential as a novel bioengineered tissue substitute for corneal surface transplantation in clinical applications. Full article

Periodontal and alveolar bone regeneration requires coordinated angiogenic and osteogenic responses supported by biomimetic scaffolds. This study compared three-dimensional bioprinted hydroxyapatite–acrylated palm olein (3D-HA–APO) scaffold formulations containing 5%, 7% and 10% (w/v) hydroxyapatite (HA), designated F1, F2 and F3, respectively. Human umbilical vein endothelial cells were cultured on the scaffolds, and background-corrected soluble vascular endothelial growth factor (VEGF) concentrations in culture supernatants were quantified by enzyme-linked immunosorbent assay (ELISA). Angiogenic-related responses of human periodontal ligament stem cells were assessed by VEGF and cluster of differentiation 31 (CD31) immunofluorescence after endothelial induction, while alkaline phosphatase (ALP) activity in construct lysates was used as an indicator of early osteogenic activity. Soluble VEGF concentrations increased from F1 to F3, with significant differences between all formulations. VEGF-associated signal proportions differed among formulations, with F3 significantly higher than F1. CD31-associated signal proportions increased progressively from F1 to F3, with significant differences between all formulation pairs. ALP activity increased over time in all scaffold groups, and F3 generally showed the highest activity from Day 4 onwards. Overall, F3 showed the most favourable formulation-level profile across the selected angiogenic-related and early osteogenic outcomes. Full article

Lipid-rich matrices can protect probiotics by limiting direct exposure to moisture, oxygen, and gastrointestinal stressors. However, triglycerides are chemically dynamic during storage, and differences in fatty acid structure and oxidation susceptibility may determine whether they exert protective or detrimental effects. In this study, tricaprylin, triolein, and trilinolein were evaluated as post-drying lipid storage matrices for freeze-dried Lactiplantibacillus plantarum 124 during storage at 25 °C, and 37 °C was used to accelerate lipid oxidation. Survival during storage, fatty acid chain retention, oxidation-derived products, stress tolerance, qualitative confocal imaging of membrane-integrity patterns, and transcriptomic responses were analyzed. After 30 d at 25 °C, log reductions were 0.30, 0.24, and 0.24 log10 units in the tricaprylin, triolein, and trilinolein groups, respectively, compared with 0.60 log10 units in the oil-free control, defining a common protective window. Tricaprylin showed the highest fatty acid chain retention, whereas trilinolein exhibited the greatest loss and strongest oxidative change. GC–MS detected no representative oxidation-derived products in tricaprylin, while unsaturated triglycerides generated dimethyl azelate and methyl 9-oxononanoate. Cells recovered from the protective window showed improved acid and bile tolerance, with survival increasing from 30.48% to 53.43–55.65% and from 14.85% to 22.49–27.79%, respectively. Confocal imaging further showed better-preserved membrane-integrity patterns in the triglyceride-treated groups after acid exposure. Transcriptomics indicated enhanced transport, redox, DNA-related, and cell-envelope responses, accompanied by reduced translation and growth-associated metabolism. Within the experimental conditions tested, these results suggest that triglyceride-associated attenuation of viability loss varies among triglyceride systems and across storage stages, while excessive oxidation of unsaturated triglycerides may weaken probiotic stability. Full article

Regular exercise mediates inter-tissue communication between skeletal muscle and the immune system through skeletal muscle-derived secretory factors, providing an important molecular basis for the beneficial effects of exercise on chronic inflammation, metabolic dysregulation, and impaired tissue repair. As key effector cells of the innate immune system, macrophages do not simply conform to a dichotomous classification of classically activated M1 macrophages and alternatively activated M2 macrophages; rather, their functional states constitute a dynamic spectrum shaped by exercise load, recovery time window, tissue microenvironment, and disease context. This review focuses on recent advances in exercise-induced skeletal muscle secretory factors involved in macrophage functional remodeling. Representative signals, including interleukin-6 (IL-6), irisin, meteorin-like protein (METRNL), fibroblast growth factor 21 (FGF21), oncostatin M (OSM), decorin, myostatin, chemokines, and extracellular vesicles, are systematically summarized in terms of their exercise responsiveness, evidence for skeletal muscle origin, and evidence supporting macrophage regulation. Based on these dimensions, an evidence-strength grading framework is further proposed. Moreover, this review integrates key signaling axes, including glycoprotein 130 (gp130)/Janus kinase (JAK)/signal transducer and activator of transcription (STAT), signal transducer and activator of transcription 6 (STAT6)/peroxisome proliferator-activated receptor gamma (PPARγ), AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2)/nuclear factor kappa B (NF-κB), transforming growth factor beta (TGF-β)/Smad, and chemokine receptor pathways, to explain how exercise-induced secretory networks participate in the dynamic regulation of the macrophage functional spectrum through immune cell recruitment, inflammatory clearance, immunometabolic reprogramming, matrix remodeling, and repair-niche formation. Current evidence indicates the translational potential of exercise-induced skeletal muscle secretory factors in skeletal muscle repair, metabolic inflammation, aging-related functional decline, and cancer rehabilitation. However, this field still faces several major challenges, including insufficient tracing of skeletal muscle-derived signals, limited direct causal validation, a lack of human tissue-level evidence, and unclear exercise dose–response relationships. Future studies should combine tissue-specific genetic interventions, receptor blockade, single-cell and spatial omics, metabolic flux analysis, and standardized human exercise interventions to further clarify the mechanistic basis and application boundaries of exercise-induced skeletal muscle–macrophage communication, thereby providing a theoretical foundation for precision exercise prescription and chronic inflammation intervention. Full article

The functional expression of plant growth-promoting (PGP) traits in soil actinobacteria is conditioned by abiotic factors, yet the combined effects of pH and temperature on their metabolic profiles and the stability of these profiles after encapsulated formulation and post-processing stress remain insufficiently characterized. This study aimed to evaluate the physiological plasticity of native actinobacteria and the expression of plant growth-promoting (PGP) traits under different pH and temperature conditions, as well as their stability after encapsulation, dehydration, and exposure to UV irradiation. Strains isolated from a semi-arid agricultural soil were analyzed to determine their ability to produce indole-3-acetic acid (IAA), siderophores, and phosphatases, as well as their ability to fix nitrogen, degrade cellulose, and tolerate salt stress. Temperature and pH significantly affected all evaluated PGP traits (p < 0.001), and their expression was not directly associated with biomass production. Two strains, S1 and S4, exhibited the highest overall PGP indices. Strain S1 maximized IAA and siderophore production under neutral conditions (pH 7.0, 30 °C), whereas strain S4 maintained more stable phosphatase activity across the tested pH and temperature ranges. Cell viability remained above 85% after encapsulation and dehydration. Dehydration enhanced IAA and siderophore production in strain S1, while strain S4 exhibited transient metabolic activation under UV irradiation in non-dehydrated capsules. The encapsulation matrix preserved cell viability more effectively than it preserved the complete PGP functional profile, indicating that viability alone is an insufficient criterion for evaluating the technological success of alginate-based bioinoculant formulations. These findings highlight the importance of integrating environmental preconditioning and functional stability assessments into the development of robust microbial bioinoculants adapted to agricultural systems subjected to fluctuating environmental conditions. Full article

Candida albicans biofilms are a major cause of persistent infections and contribute to antifungal resistance as well as limitations in drug delivery. Targeting virulence traits such as biofilm formation and hyphal transition represents an effective strategy for controlling fungal pathogenicity without exerting strong selective pressure on planktonic growth. In this study, a library of structurally diverse benzophenone derivatives was screened to identify compounds with antibiofilm and anti-hyphal activities against azole-resistant C. albicans. Most benzophenone derivatives exhibited weak antifungal activity (MIC ≥ 200 µg/mL). However, several halogenated benzophenones markedly suppressed biofilm formation. Among them, decafluorobenzophenone at 10 µg/mL displayed the strongest inhibition, reducing biofilm formation to approximately 1–2% of control levels while maintaining substantial planktonic cell viability. Microscopy confirmed hyphal suppression, while qRT-PCR showed a 36-fold reduction in ALS3 expression. These findings indicate that multi-halogenated benzophenones act primarily as anti-virulence agents targeting biofilm formation and hyphal development. Molecular docking suggested a possible interaction of decafluorobenzophenone with the Als3 binding pocket. Decafluorobenzophenone showed low toxicity, with unaffected Caenorhabditis elegans viability at 10 µg/mL, plant germination at 100 µg/mL, and only slight hemolysis at 100 µg/mL. The results highlight halogen substitution as a key structural determinant and identify benzophenone scaffolds as promising leads for developing novel antibiofilm strategies against azole-resistant Candida infections. Full article